Diagnosis and management of chronic kidney disease docx

Urine dipstickabnormalitysection 2.2.1 to 2.2.2 Abnormal measure ofrenal function section 2.3 Kidneystructuralabnormality Blood tests Creatinine/eGFR section 2.3 Old dataOther tests Urin

Scottish Intercollegiate Guidelines Network

Diagnosis and management of chronic kidney disease

A national clinical guideline

2008103

1++ High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias

1+ Well conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias

1 - Meta-analyses, systematic reviews, or RCTs with a high risk of bias

2++ High quality systematic reviews of case control or cohort studies

High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal

2+ Well conducted case control or cohort studies with a low risk of confounding or bias and a

moderate probability that the relationship is causal

2 - Case control or cohort studies with a high risk of confounding or bias and a significant risk that

the relationship is not causal

3 Non-analytic studies, eg case reports, case series

4 Expert opinion

GRADES OF RECOMMENDATION

Note: The grade of recommendation relates to the strength of the evidence on which the

recommendation is based It does not reflect the clinical importance of the recommendation.

A At least one meta-analysis, systematic review, or RCT rated as 1++,

and directly applicable to the target population; or

A body of evidence consisting principally of studies rated as 1+,

directly applicable to the target population, and demonstrating overall consistency of results

B A body of evidence including studies rated as 2++,

directly applicable to the target population, and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 1++ or 1+

C A body of evidence including studies rated as 2+,

directly applicable to the target population and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 2++

D Evidence level 3 or 4; or

Extrapolated evidence from studies rated as 2+

GOOD PRACTICE POINTS

 Recommended best practice based on the clinical experience of the guideline development group

NHS Quality Improvement Scotland (NHS QIS) is committed to equality and diversity This

guideline has been assessed for its likely impact on the six equality groups defined by age, disability, gender, race, religion/belief, and sexual orientation

For the full equality and diversity impact assessment report please see the “published guidelines” section of the SIGN website at www.sign.ac.uk/guidelines/published/numlist.html The full report

in paper form and/or alternative format is available on request from the NHS QIS Equality and

Diversity Officer

Every care is taken to ensure that this publication is correct in every detail at the time of publication However, in the event of errors or omissions corrections will be published in the web version of this document, which is the definitive version at all times This version can be found on our web site

www.sign.ac.uk

Diagnosis and management of chronic kidney disease

A national clinical guideline

2008

isBn 978 1 905813 30 8 Published 2008

SIGN consents to the photocopying of this guideline for the purpose of implementation in NHSScotland

scottish intercollegiate guidelines network elliott house, 8 -10 hillside crescent

edinburgh eh7 5ea www.sign.ac.uk

1 introduction 1

1.1 The need for a guideline 1

1.2 Remit of the guideline 1

1.3 Statement of intent 2

2 risk factors, diagnosis and classification 3

2.1 Detection of individuals at higher risk of developing chronic kidney disease 3

2.2 Detecting kidney damage 5

2.3 Measuring renal function 8

2.4 Comparing renal function tests 9

2.5 Classification of chronic kidney disease 11

2.6 Clinical evaluation and referral 13

3 treatment 15

3.1 Lowering blood pressure 15

3.2 Reducing proteinuria 16

3.3 Angiotensin converting enzyme inhibitors and angiotensin receptor blockers 16

3.4 Non-dihydropyridine calcium channel blockers 20

3.5 Lipid lowering 20

3.6 Antiplatelet therapy 21

3.7 Dietary modification 22

3.8 Lifestyle modification 23

3.9 Other interventions 24

3.10 Treatments to improve quality of life 24

3.11 Managing renal bone disease 27

3.12 Managing metabolic acidosis 28

4 Provision of information 29

4.1 Sample information leaflet 29

4.2 Sources of further information 31

5 implementing the guideline 32

5.1 Resource implications of key recommendations 32

5.2 Auditing current practice 34

5.3 Advice to NHSScotland from the Scottish Medicines Consortium 35

6 the evidence base 36

6.1 Systematic literature review 36

6.2 Recommendations for research 36

6.3 Review and updating 36

7 Development of the guideline 37

7.1 Introduction 37

7.2 The guideline development group 37

7.3 Acknowledgements 38

7.4 Consultation and peer review 38

abbreviations 40

annex 1 key questions used to develop the guideline 42

annex 2 expressions of urinary protein concentration and their approximate equivalents and clinical correlates 44

references 45

1 introduction

1.1 the neeD for a guiDeline

Chronic kidney disease (CKD) is a long term condition caused by damage to both kidneys.There

is no single cause and the damage is usually irreversible and can lead to ill health In some

cases dialysis or transplantation may become necessary It is only relatively recently that the

epidemiology of CKD has been studied in detail with the finding that it is more common than

previously thought.1,2,3 The average prevalence has been reported at 11% in USA and Europe

(excluding those on dialysis or with a functioning transplant).4 Diabetes mellitus, which is also

becoming more common, is one cause of CKD Chronic kidney disease is seen more frequently

in older people and therefore is likely to increase in the population as a whole.2

People with CKD are at higher risk of cardiovascular disease and they should be identified

early so that appropriate preventative measures can be taken In the early stages of CKD people

may be unaware that they have any illness and a blood or urine test may be the only way it

is discovered Establishing which conditions predispose to CKD identifies those who should

have the necessary blood or urine tests Early detection of CKD can establish if kidney disease

is likely to be progressive allowing appropriate treatment to slow progression

Previous renal clinical guidelines have focused on patients with end-stage renal disease (ESRD).5-7

End-stage renal disease, also called established renal failure, is chronic kidney disease which

has progressed so far that the patient’s kidneys no longer function sufficiently and dialysis or

transplantation become necessary to maintain life Given the increased recognition of CKD at

earlier stages, the risks of cardiovascular disease and the potential for the disease to progress

towards ESRD, guidelines for early identification and management of patients are now a

priority

1.2 remit of the guiDeline

1.2.1 OvERALL ObjECTIvES

This guideline covers three main areas Firstly, the evidence for the association of specific risk

factors with CKD is presented to help identify which individuals are more likely to develop

CKD Secondly, guidance is provided on how to diagnose CKD principally using blood and

urine tests Thirdly, the guideline contains recommendations on how to slow the progression

of CKD and how to reduce the risk of cardiovascular disease

The management of complications of CKD, such as anaemia and bone disease, is also discussed

Evidence for the best psychological and social support for patients and what information they

need to take an optimal part in the management of their condition has been identified and

incorporated

The management of patients with ESRD or patients with acute kidney disease is excluded

from this guideline Patients with clinical features suggestive of a primary renal diagnosis, eg

glomerulonephritis presenting with nephrotic syndrome, or renal disease secondary to vasculitis

presenting with haematuria and proteinuria, should be referred to the renal service Their

specific management is not part of this guideline The management of complications associated

with CKD during pregnancy is a specialised area which is not covered in this guideline This

guideline relates to adult patients only (≥18 years)

1.2.2 TARGET USERS OF THE GUIDELINE

This guideline will be of value to all health professionals in primary and secondary care involved

in the detection and management of patients with CKD Specifically it should be of use to:patients and their carers

cardiologists, vascular surgeons and those working in the care of the elderly

trainees and medical students

ƒ

1.3 statement of intent

This guideline is not intended to be construed or to serve as a standard of care Standards

of care are determined on the basis of all clinical data available for an individual case and are subject to change as scientific knowledge and technology advance and patterns of care evolve Adherence to guideline recommendations will not ensure a successful outcome in every case, nor should they be construed as including all proper methods of care or excluding other acceptable methods of care aimed at the same results The ultimate judgement must be made by the appropriate healthcare professional(s) responsible for clinical decisions regarding

a particular clinical procedure or treatment plan This judgement should only be arrived at following discussion of the options with the patient, covering the diagnostic and treatment choices available It is advised, however, that significant departures from the national guideline

or any local guidelines derived from it should be fully documented in the patient’s case notes

at the time the relevant decision is taken

1.3.1 ADDITIONAL ADvICE TO NHSSCOTLAND FROM NHS QUALITY IMPROvEMENT

SCOTLAND AND THE SCOTTISH MEDICINES CONSORTIUM

NHS QIS processes multiple technology appraisals (MTAs) for NHSScotland that have been produced by the National Institute for Health and Clinical Excellence (NICE) in England and Wales

The Scottish Medicines Consortium (SMC) provides advice to NHS boards and their Area Drug and Therapeutics Committees about the status of all newly licensed medicines and any major new indications for established products

SMC advice and NHS QIS validated NICE MTAs relevant to this guideline are summarised in the section implementating the guideline

All patients with evidence of persisting kidney damage, ie for >90 days, are defined as having

CKD Kidney damage refers to any renal pathology that has the potential to cause a reduction

in renal functional capacity This is most usually associated with a reduction in glomerular

filtration rate (GFR) but other important functions may be lost without this occurring

This section covers potential risk factors for the development of CKD (see section 2.1); how

kidney damage or excretory function can be measured (see sections 2.2 to 2.4) and a classification

system for CKD (see section 2.5) A sample diagnostic pathway is discussed in section 2.6.

2.1 Detection of inDiviDuals at higher risk of DeveloPing chronic

kiDney Disease

Epidemiology reveals an association between a number of clinical characteristics and the

development of chronic kidney disease For many potential risk factors, the supporting evidence

is inconclusive, of poor methodological quality or does not clearly establish a causal relationship

Decisions regarding risk factor modification should be taken on an individual basis

Factors which may be complicated by renal disease, but are not risk factors for its development,

such as lithium toxicity or lupus nephritis are not considered here

2.1.1 DIAbETES MELLITUS

Diabetic nephropathy is a renal complication of diabetes mellitus Diabetes is the commonest

cause of ESRD requiring renal replacement therapy.8-10 The age-adjusted incidence of all-cause

ESRD in men with diabetes is more than 12 times greater than in men without diabetes (199.0

vs 13.7 cases per 100,000 person years; relative risk (RR) 12.7; 95% confidence interval (CI),

10.5 to 15.4).11 This increased incidence was attributable to both diabetic and non-diabetic

nephropathy In 2005, 0.5% of the population with diabetes who were recorded in the National

Diabetes Survey were reported to be at ESRD.12

The linkage of diabetes with earlier stages of CKD is more difficult to demonstrate In one

cross-sectional study diabetes was found to be associated with CKD with the relative risk increasing

with the severity of CKD.2 In the baseline cohort analysis of a large Medicare American study

(n=1,091,201 aged >65 years) the presence of diabetes was found to double the risk of

developing CKD compared with those without diabetes (odds ratio (OR) 2.04; 95% CI 2.00

to 2.09, p<0.0001).17

When followed up over two years, people from this cohort with diabetes, but without known

CKD, developed kidney damage at a rate of 0.2 per 100 patient years as compared with 0.04

per 100 patient years for people without diabetes The progression of disease was also more

frequent in patients with CKD and diabetes with 3.4 per 100 patient years requiring dialysis as

compared with CKD patients without diabetes who reached this end point at less than half the

rate (1.6 per 100 patient years; p<0.0001)

In a community based longitudinal cohort study of patients from the Framingham Offspring

Study 2,585 individuals without evidence of CKD were monitored over 12 years In multivariate

analysis those with diabetes at baseline had an increased rate of development of CKD (OR 2.60;

95% CI 1.44 to 4.70) over a 12 year period.13

In contrast to these positive associations a large cross-sectional Australian cohort study (11,247

patients) did not find an association between diabetes and the presence of CKD.14

Within the limitations of cross-sectional cohort methodology and longitudinal cohort data,

diabetes is a significant risk factor for CKD and individuals with both diabetes and CKD appear

to be more likely to progress to end-stage renal disease

This supports current recommendations in national guidelines on the surveillance of patients

with diabetes for CKD The optimal surveillance strategy has not been defined.15,16

D all patients with diabetes should have regular surveillance of renal function.

Patients who are on antihypertensive or lipid lowering therapy should have renal function

;assessed at least annually

2.1.3 SMOKING

A good quality Swedish case control study provides supportive evidence for current or former history of smoking (at five years before survey) as a significant risk factor for CKD in a community based population.20 Odds ratios increased with increasing frequency and duration of smoking

A ‘pack year’ is calculated by multiplying the number of packs of cigarettes smoked per day by the number of years an individual has smoked More than 15 pack years of smoking increased the risk of CKD significantly (16-30 pack years: OR 1.32; >30 pack years: OR 1.52)

c smoking should be considered as a risk factor for the development of chronic kidney disease.

See section 3.8.2 for lifestyle modification advice to reduce cardiovascular risk.

2.1.4 CARDIOvASCULAR DISEASE

One cross-sectional study on an American Medicare population (aged >65 years) was identified Patients with atherosclerotic vascular disease were 1.5 times more likely to develop CKD than those without, and patients with congestive cardiac failure were nearly twice as likely to do

so.17 The Medicare population was selective in excluding, for example, certain patients with health insurance There were also problems of definition and coding since classification was based on diagnostic coding at billing which does not distinguish between CKD stages

2.1.5 AGE

Two retrospective studies, were consistent in showing that age was a significant risk factor; the first examined <65 year olds compared to >65 year olds with a resultant odds ratio of 101.5 (95% CI, 61.4 to 162.9) indicating increased risk of renal impairment at an older age.14 The second showed increasing relative risks in a population>65 years old, albeit with overlapping confidence intervals.17

The Framingham Offspring study established a graded risk associated with age (OR of 2.36 per 10 year age increment; 95% CI 2.00 to 2.78).13 There is uncertainty as to whether age associated decline in GFR is pathological and should be afforded the same significance as declining function in other situations.21

2.1.6 CHRONIC USE OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

Two retrospective single cohort studies of physicians22 and nurses,23 examined non-steroidal anti-inflammatory drug (NSAID) use as a risk factor for developing CKD Neither found chronic use of aspirin or NSAIDs in prescribed doses to be significant risk factors over a period of 14 and 11 years respectively, although one found use of paracetamol to be so.23 Selection bias was a significant limitation in both studies, since subjects were not representative of the general population, and small proportions of the original sample populations were included in the final analyses

The use of NSAIDs in patients with established CKD is not addressed in this guideline

2.1.7 ObESITY AND SOCIOECONOMIC STATUS

One cross-sectional Dutch study on obesity as a risk factor for CKD concluded that bMI (body

mass index) had no effect on the prevalence of CKD, although some evidence was presented for a

central pattern of fat distribution being associated with CKD compared with a peripheral pattern.24

This retrospectively obtained evidence had limitations, including low response rate

An American cohort study concluded that white men and African-American women living in

an area of low socioeconomic status had a greater risk of CKD progression than white men and

African-American women living in a higher designated area No similar CKD risk progression

was found for white women and African-American men.25 There were methodological limitations

in this study and little information on sampling and attrition rates was available

A Swedish, community based case control study showed that lower household and individual

level socioeconomic status and fewer years of education were significant risk factors for CKD

in the Swedish population.26

c low socioeconomic status should be considered as a risk factor for the development

of chronic kidney disease.

2.2 Detecting kiDney Damage

Kidney damage may be detected either directly or indirectly Direct evidence may be found on

imaging or on histopathological examination of a renal biopsy A range of imaging modalities

including ultrasound (see section 2.2.3), computed tomography (CT), magnetic resonance

imaging (MRI) and isotope scanning can detect a number of structural abnormalities including

polycystic kidney disease, reflux nephropathy, chronic pyelonephritis and renovascular disease

Renal biopsy histopathology is most useful in defining underlying glomerular disease such as

immunoglobulin A (IgA) nephropathy or focal glomerulosclerosis

Indirect evidence for kidney damage may be inferred from urinalysis Glomerular inflammation

or abnormal function can lead to leakage of red blood cells or protein into the urine which

in turn may be detected as proteinuria or haematuria (see sections 2.2.1 and 2.2.2) Urinary

abnormalities may have alternative causes unrelated to kidney dysfunction and there are

methodological issues associated with their measurement

2.2.1 PROTEINURIA

Proteinuria is associated with cardiovascular and renal disease and is a predictor of end organ

damage in patients with hypertension Detection of an increase in protein excretion is known

to have both diagnostic and prognostic value in the initial detection and confirmation of renal

disease.27

In evaluating the diagnostic accuracy of tests of proteinuria, measurement of protein (or albumin)

excretion in a timed urine collection over 24 hours has been used as a reference standard.28

Annex 2 explains the relationship between urinary protein (and albumin) concentrations

expressed as a ratio to creatinine and other common expressions of their concentration

urine dipstick testing

Although urine dipstick testing is widely available, convenient and relatively cheap, evidence

for its diagnostic accuracy is limited to studies that have compared dipstick testing with either

protein or albumin excretion in a timed urine collection over 24 hours.29-36 Pooling the six

obstetric studies 29-34 gives a positive likelihood ratio of 3.48 (95% CI 1.66 to 7.27) and a negative

likelihood ratio of 0.6 (95% CI 0.45 to 0.8) for predicting 300 mg/24-hour proteinuria at 1+ or

more (likelihood ratios of >5 or <0.2 provide good evidence of the diagnostic performance

of tests in rule-in and rule-out modes respectively).27

The accuracy of automated analysis is greater than visual analysis of urine dipsticks In one

study, the positive likelihood ratio was 4.27 (95% CI 2.78 to 6.56) and negative likelihood

ratio 0.22 (95% CI 0.14 to 0.36) for automated urinalysis compared with 2.27 (95% CI 1.47 to

3.51) and 0.64 (95% CI 0.49 to 0.82) for visual urinalysis.38

The existing limited evidence base does not indicate that dipstick testing can reliably be used

to diagnose the presence or absence of proteinuria Automated urinalysis warrants further evaluation

There is evidence from the Multiple Risk Factor Intervention Trial (MRFIT), that dipstick proteinuria in men predicts long term risk of ESRD.39 In the MRFIT cohort the hazard ratio for ESRD over 25 years for patients with ≥1+ dipstick proteinuria (3.1, 95% CI 1.8 to 5.4) was higher than for an estimated GFR of <60 ml/min/1.73 m2 (2.4, 95% CI 1.5 to 3.8) In addition, dipstick proteinuria identifies individuals at higher cardiovascular risk.40-42

A systematic review of the practice of excluding urinary tract infection (UTI) in patients with proteinuria found that symptomatic, but not asymptomatic UTI is commonly associated with proteinuria/albuminuria.43 A threshold above which proteinuria can be definitively attributed

to intrinsic renal disease as opposed to a superimposed UTI could not be identified

Protein/creatinine ratio

A systematic review comparing measurement of protein/creatinine ratio (PCR) on a random urine sample with 24-hour protein excretion included studies carried out during pregnancy and studies performed in renal and rheumatology outpatient clinics.27 Likelihood ratios <0.2 were reported in most of the studies, supporting the diagnostic performance of PCR as a test

of exclusion There was a high prevalence of proteinuria in the populations studied, and these findings should be extrapolated with caution to populations with a lower prevalence

Protein/creatinine ratio measured in early morning or random urine samples is at least as good

as 24-hour urine protein estimation at predicting the rate of loss of GFR in patients with CKD who do not have diabetes.44

albumin/creatinine ratio

A meta-analysis of ten studies in patients with diabetes compared a random albumin/creatinine ratio (ACR) measurement with albumin excretion rate (AER) from overnight or 24-hour timed samples.45 In seven studies ACR was compared with 24-hour albumin excretion The performance

of ACR was expressed as a summary diagnostic odds ratio of 45.8 (95% CI 28.5 to 73.4) The use of ACR could save the inconvenience of collecting a timed urine specimen with only a negligible loss of case detection when compared with AER The ACR data reported in patients with hypertension are similar.46

Microalbuminuria predicts ESRD in people with diabetes.47 Combined estimates of relative risk quoted for microalbuminuria (compared with normoalbuminuria) include an RR of ESRD of 4.8 (95% CI 3.0 to 7.5) in people with type 1 diabetes and 3.6 (95% CI 1.6 to 8.4) in people with type 2 diabetes Although much of the evidence concerns measures of albuminuria other than ACR, three studies48-50 use this measure Albumin/creatinine ratio is also a marker of renal insufficiency in non-diabetic subjects,51 and in the Heart Outcomes Prevention Evaluation (HOPE) cohort (subjects with cardiovascular disease, or diabetes and one or more cardiovascular risk factor), baseline microalbuminuria, as detected by ACR, predicted clinical proteinuria in both diabetic and non-diabetic subjects.52

In the HOPE cohort and in other studies, microalbuminuria also predicted major cardiovascular events, with an adjusted relative risk of 1.83 (95% CI 1.64 to 2.05) over the period of the study (median 4.5 years) For every 0.4 mg/mmol increase in ACR, the adjusted hazard increased

by 5.9%.53-56

summary of evidence and other considerations

Overall, the evidence suggests that urine dipstick testing cannot reliably be used to diagnose the presence or absence of proteinuria although there is evidence that dipstick proteinuria (≥1+) predicts ESRD and cardiovascular disease There is no evidence that isolated asymptomatic UTI causes proteinuria/albuminuria PCR and ACR are accurate rule-out tests in populations with a high probability of proteinuria PCR and ACR predict subsequent progression of renal disease ACR has also been shown to predict cardiovascular disease, although similar evidence for PCR was not identified

The measure of protein excretion that is used in a particular context will be influenced by other

considerations For example, because of its widespread availability, convenience and relatively

low cost, urine dipstick testing will often be the initial measure used Where confirmation

is required for diagnostic purposes, the lower cost of PCR should be weighed against the

superior accuracy of ACR at low concentrations The role of microalbuminuria in the detection

and management of diabetic nephropathy means that ACR will be preferred in patients with

B in patient groups with a high prevalence of proteinuria without diabetes

protein/creatinine ratio may be used to exclude chronic kidney disease.

D in patients with established chronic kidney disease and without diabetes, measurement

of protein/creatinine ratio may be used to predict risk of progressive disease.

Dipstick proteinuria (≥1+) can be used to identify patients at risk of subsequent end-

;

stage renal disease and cardiovascular disease

Urine dipstick testing cannot be used reliably in isolation to diagnose the presence or

;

absence of proteinuria

2.2.2 HAEMATURIA

Macroscopic or frank haematuria is often a manifestation of urinary tract malignancy Exclusion

of infection followed by urological investigation is the most appropriate initial step.57

Microscopic haematuria may indicate significant pathology including infection, malignancy

and other forms of kidney damage A single positive dipstick test is not sufficient to indicate

pathology as it is a common finding with rates ranging from 1.7% in a UK student population58

to 18.1% in a US study of first order relatives of patients with hypertension, diabetes or CKD.59

The UK student study showed that repeat analysis was negative in 60% of cases indicating that

many patients have transient haematuria

Isolated microscopic haematuria is associated with a modest increased risk of progressive

kidney disease A large Australian cross-sectional cohort study found that individuals with

isolated haematuria had a greater risk of CKD, defined by GFR <60 (OR 1.4).14 A japanese

cohort study involving population screening where patients were followed up over 17 years

found that having 2+ haematuria conveyed a relative risk for requiring dialysis of 2.4.60 Another

japanese study identified that persisting haematuria carried a 0.7% risk of developing CKD at

10 years in working men.61 When haematuria and proteinuria were both detected the risk of

subsequent CKD rose to 12% over this period

Although the risk of developing progressive CKD in patients with isolated microscopic

haematuria is low, renal or urinary pathology is often present The japanese study followed 165

patients with persisting haematuria and 13 of 17 patients who underwent renal biopsy had IgA

nephropathy.61 A similar rate of IgA disease was detected in a UK biopsy study.62

Isolated microscopic haematuria may be present in other glomerulonephritic conditions

including systemic vasculitis This is most often seen in the context of acute renal disease

A health technology assessment examining the most effective method to evaluate haematuria

concluded that there were insufficient data to derive an evidence based algorithm for the

evaluation of haematuria.63 A strategy based on expert opinion was reviewed in the context

of international guidelines.64-66 The assessment recommended that after the exclusion of

infection, isolated microscopic haematuria should be evaluated to exclude malignancy of the

urinary tract, with more urgent assessment required in those over 50 years of age If coexistent

2.2.3 RENAL TRACT ULTRASOUND

Ultrasound is the optimal first line test for imaging the renal tract in patients with CKD and identifies obstructive uropathy, renal size and symmetry, renal scarring and polycystic disease.67

Large studies of ultrasound screening in asymptomatic members of the general population have been carried out in japanese adults,68 in older American adults69 and in older German adults.70 They demonstrated an incidence of obstructive uropathy of between 0.13-0.34% of the population The German study found renal calculi in 2.14% and renal asymmetry in 0.40% Additional minor findings were found in 13%

No evidence was identified on the usefulness of renal ultrasound alone in the diagnosis of CKD

Ultrasound is the imaging modality of choice in the evaluation of patients with suspected

;chronic kidney disease

2.3 measuring renal function

2.3.1 DEFINING GLOMERULAR FILTRATION RATE

The glomerular filtration rate is defined as the volume of plasma which is filtered by the glomeruli per unit time and is usually measured by estimating the rate of clearance of a substance from the plasma Glomerular filtration rate varies with body size and conventionally is corrected

to a body surface area (bSA) of 1.73 m2, the average bSA of a population of young men and women studied in the mid-1920s.71

One study has reported that the delay in separating serum from venous blood samples may affect some creatinine measurements, and result in CKD misclassification.78 Leaving clotted blood unseparated increased creatinine concentration significantly after 16 hours (p<0.001)

by 48 hours creatinine concentrations had increased above the baseline measurement (samples separated after 30 minutes) on average by 29% (range 21–63%) The CKD staging of 32% of patients in the study changed as a result of delaying sample separation for 24 hours

Depending on the creatinine method used, staging of chronic kidney disease should not

3

3 4

Prediction equations improve the inverse correlation between serum creatinine and GFR by

taking into account confounding variables such as age, sex, ethnic origin and body weight

The formula developed by Cockcroft and Gault to estimate creatinine clearance,80 and the

four-variable formula derived from the Modification of Diet in Renal Disease (MDRD) study to

estimate GFR,81 are the most widely used of these prediction equations The Cockcroft-Gault

formula incorporates age, sex and weight in addition to creatinine, while the four-variable

MDRD formula incorporates age, sex, and ethnicity, but not weight

2.3.4 CYSTATIN C

Serum concentrations of the low molecular weight protein cystatin C correlate inversely with

GFR The concentration of cystatin C is independent of weight and height, muscle mass,

adult age or sex and is largely unaffected by intake of meat or non-meat-containing meals.77

Cystatin C has become a candidate marker for GFR assessment

2.3.5 OTHER MARKERS

various other markers have been used to estimate clearance, including inulin, iohexol

and radioisotopic markers such as 51Cr-ethylenediaminetetraacetic acid (EDTA),

99mTc-diethylenetriaminepentaacetic acid (DTPA) and 125I-iothalamate Measurement of any

of these markers is too costly and labour intensive to be widely applied For the purposes of

evaluating methods of GFR assessment, inulin clearance is widely regarded as the most accurate

(gold standard) estimate of GFR,82 whilst the radioisotopic methods listed above are accepted

as validated reference standards.83,84

2.4 comParing renal function tests

Forty one hospital based studies were identified that compared measures of renal function with

a gold standard (inulin clearance) or validated reference standard (in most cases 51Cr-EDTA

clearance) The appropriateness of generalising from hospital based evidence to all patients at

risk of CKD is not clear In addition, the accuracy of prediction equations may be influenced

by the methods used to measure creatinine, further limiting the conclusions that can be drawn

from some of the studies cited

2.4.1 PREDICTION EQUATIONS

comparison with other methods

Prediction equations are consistently more accurate than serum creatinine in the assessment of

GFR.85-97 An estimated GFR of less than 60 ml/min/1.73 m2 is associated with an increased risk

of the major adverse outcomes of CKD (impaired kidney function, progression to kidney failure

and premature death from cardiovascular disease).98-101,125 Prediction equations perform as well

as or better than 24-hour urine creatinine clearance in all but one study (see section 2.4.4).102

Only two studies out of thirteen suggest that cystatin C is superior to prediction equations

(specifically Cockcroft-Gault);92,93 most studies show comparable performance

comparison of different prediction equations

Studies comparing the four-variable (also known as simplified) MDRD with Cockcroft-Gault give

inconsistent results, though a majority indicate either comparable performance or superiority

of MDRD over Cockcroft-Gault.88-90,92,102-111 These studies include the largest by far (>2,000

patients), in which comparison was made across a range of subgroups defined according to

age, sex, true GFR, and bMI.106 This study concluded that the MDRD formula provided more

reliable estimations of kidney function than the CG formula

Only three out of 14 studies91,112,113 suggest that Cockcroft-Gault is better In these studies, the

poorer performance of MDRD may reflect the older age of the patients, or the high GFRs of the

subjects studied (MDRD is less accurate and precise in estimating normal renal function).106

The performance of Cockcroft-Gault and simplified MDRD equations is differentially affected

by true GFR, age, sex, bMI and creatinine methodology, and these factors may explain some

of the inconsistent findings

In general, both MDRD and Cockcroft-Gault perform better at low GFR, probably reflecting the populations in which they were developed The MDRD equation is preferred by most laboratories estimating GFR

limitations of prediction equations

The MDRD equation is widely used to estimate GFR in order to facilitate the detection of CKD Although MDRD is superior to serum creatinine in the assessment of GFR (see section 2.4.2),

there are several problems with this approach

The MDRD equation is not completely accurate, and the extent of its inaccuracy varies between different patient groups Even in the MDRD study population (patients with CKD) which was used to validate the equation, 9% of GFR estimates were 30% or more outwith the isotope-measured values.81 Estimates of GFR are even less accurate in populations with higher GFR (≥60 ml/min/1.73 m2).106 The tendency of MDRD to underestimate true GFR in this range results in a significant risk of false positive diagnosis of CKD This makes it difficult to interpret estimated GFR values of ≥60 ml/min/1.73 m2

The best approach may be to report a specific value only if the estimated GFR is <60 ml/min/1.73 m2 In patients with a reported eGFR of ≥60 ml/min/1.73 m2, serum creatinine can still be used to assess trends in renal function

In addition, the MDRD equation is only validated for use in Caucasian and African-American populations validation studies in other ethnic groups are underway Groups in which the equation has not been fully validated include older patients, pregnant women, patients with serious comorbid conditions, and patients with extremes of body size, muscle mass, or nutritional status Application of the equation to these patient groups may lead to errors in GFR estimation.114

Finally, estimates of GFR obtained by creatinine methods that are biased compared to the creatinine assay used in the original MDRD study can be substantially different In one example, reanalysis of data after standardisation of one creatinine assay to the MDRD assay changed a pre-standardisation mean positive bias for the MDRD equation of 6.4 ml/min/1.73 m2 compared with 51Cr-EDTA91 to no significant bias.115

If accuracy is an overriding consideration (eg for potential kidney donors or administration of drugs that are excreted by, or toxic to, the kidneys), a more accurate method of measurement, such as one of the validated reference methods listed in section 2.3.5 is required

Differences between populations studied with respect to true GFR, age and sex may explain some of the inconsistencies observed

2 +

4

3

2.4.4 24-HOUR URINARY CREATININE CLEARANCE

In most studies this method performs less well than prediction equations or cystatin C,

85-87,91, 102,104, 121 although two studies found little difference.88,89 One study found it to be superior

to prediction equations in assessing GFR in normoalbuminuric type 1 diabetic patients and

healthy controls;113 this may reflect the high GFR of the study population and the carefully

controlled study conditions

2.4.5 SUMMARY

Prediction equations are more accurate than serum creatinine or 24-hour urine creatinine

clearance in the assessment of GFR 24-hour urine creatinine clearance is inconvenient and

imprecise, and offers no advantages over prediction equations in most patients The literature

comparing cystatin C with serum creatinine is inconclusive Prediction equations are at least

as good in the detection of reduced GFR as cystatin C

Drug dosing

virtually all published recommendations for dose adjustment in patients with reduced renal

function, including the british National Formulary (bNF),122 and manufacturers’ summaries of

product characteristics123 are based on creatinine clearance estimated by the Cockcroft-Gault

formula There is no evidence that this estimate can be used interchangeably with the four

variable MDRD formula The current practice of using the Cockcroft-Gault formula for drug

dosing should be continued until such evidence is forthcoming.124

c Where an assessment of glomerular filtration rate is required prediction equations

should be used in preference to 24-hour urine creatinine clearance or serum creatinine

Staging of chronic kidney disease

; (see section 2.5.1) should not be based on samples

collected after consumption of meals containing cooked meat Confirmatory samples should be taken in the fasting state

Alterations in drug dosing in patients with reduced renal function should be made on

;

the basis of creatinine clearance as estimated by the Cockcroft-Gault formula

2.5 classification of chronic kiDney Disease

A widely adopted classification of chronic kidney disease was developed by the American

National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI tm).125,126

Minor revisions have been made by the Kidney Disease Improving Global Outcomes (KDIGO)

organisation, and by a UK Consensus Conference.128

The original intention of the KDOQI group was to develop both a severity classification system

for patients with established CKD and diagnostic criteria for CKD The system suggested that

CKD could be diagnosed solely on the basis of GFR <60 ml/min/1.73 m2 As single aberrant

results are relatively common the abnormality should be present for at least three months

As GFR may decline with age GFR in the very elderly may already be at this diagnostic threshold

As this might reflect the high incidence of kidney disease in older individuals no age or sex

adjustment was made to the GFR thresholds This aspect of the diagnostic criteria has been

extensively used in many subsequent epidemiological studies that have tried to estimate the

prevalence of CKD.2 In most cases a single creatinine blood result combined with GFR prediction

equations have been used These studies reported a high prevalence of CKD in the elderly It

has since been suggested that a modestly reduced GFR in an older person may not have the

same clinical significance as an identical finding in a younger person.21,129

3 4

The guideline development group suggests that the KDOQI classification system is used only after the patient has been clinically evaluated, when it is useful for staging the severity of disease, any likely associated complications and to identify those that are most likely to progress

The KDOQI classification system should only be used to stage patients with a diagnosis

At stage 5, the suffix D indicates that the patient is on dialysis, and at stages 1-5 the suffix T indicates that the patient has a functioning kidney transplant.127

The UK Consensus Conference recommended dividing stage 3 into two parts Population studies had suggested that stage 3 CKD encompassed a large spectrum of patients most of whom were asymptomatic Complications of renal disease are far more common amongst those with a GFR below 45 and this was set as the threshold for stage 3b It was felt that these individuals were likely to require increased monitoring and treatment

The suffix p indicates significant proteinuria (>1 g per day – approximately equivalent to a protein/creatinine ratio of 100 mg/mmol) This group are at a high risk of deterioration of renal function and warrant thorough investigation and intensive management.2,128

The modified classification system is shown in Table 1

Table 1: Stratification of chronic kidney disease

1* Kidney damage with normal or raised GFR ≥902* Kidney damage with mild decrease in GFR 60-893A

3b Moderately lowered GFR

45-5930-44

5 Kidney failure (end-stage renal disease) <15Notes: *in order to diagnose stages 1 and 2 CKD, additional evidence of kidney damage must be

present, eg proteinuria.

If proteinuria (>1 g per day or >100 mg/mmol) is present the suffix p should be added.

Patients on dialysis are classified as stage 5D.

The suffix T indicates patients with a functioning renal transplant (can be stages 1-5).

2.6 clinical evaluation anD referral

No evidence was identified on how to incorporate individual markers of kidney damage or

estimation of GFR into a framework for evaluating patients as part of the diagnostic pathway

The guideline development group has developed an algorithm that can be used to evaluate

patients and plan services related to the identification of CKD (see Figure 1).

2.6.1 ALGORITHM FOR SCREENING, ASSESSMENT AND DIAGNOSIS OF PATIENTS WITH

CHRONIC KIDNEY DISEASE

Individuals with CKD are identified in many different circumstances, eg a surveillance

programmes within a diabetic clinic, as part of the evaluation of a patient with a known risk

factor for CKD or as an incidental finding during a routine health medical examination (see

Figure 1A).

A single marker is a common point of entry for an individual into the pathway of CKD evaluation

Even if there is direct evidence of kidney pathology, for example an ultrasound demonstrating

kidneys with multiple cysts, further clinical evaluation will be needed to make a firm diagnosis

and a functional assessment will be required to plan future care (see Figure 1B).

Clinical evaluation should include history taking, examination and confirmation of initial

observations All patients should have urine sent for protein quantification and a renal tract

ultrasound if there are relevant symptoms (see Figure 1C).

The exclusion of acute or ‘acute on chronic’ renal disease is of key importance If this is the

first time an abnormal creatinine has been detected, or the patient is unwell it is reasonable to

assume that this could be acute kidney injury An urgent repeat blood test will usually confirm

if there is a rapidly progressive decline in kidney function which requires specialist referral

The outcome of this evaluation should establish whether there is clear evidence of CKD Once

this is established a profile can be constructed describing the likely aetiology, the KDOQI staging

of the disease (see section 2.5.1) and an indication of any documented disease progression or

an assessment of the risk of future progression (see Figure 1D).

Urine dipstickabnormality

(section 2.2.1 to 2.2.2)

Abnormal measure ofrenal function

(section 2.3)

Kidneystructuralabnormality

Blood tests

Creatinine/eGFR

(section 2.3)

Old dataOther tests

Urine examination

Repeat samplesMicroscopyLaboratory protein

Unwell patientRapidly decliningfunctionUnexpected result

Nephrology

Nephrotic syndromeRenal biopsyUnclear clinicalpicture

Urology

Possible tumourCytoscopyOther

CKD confirmed and characterised

Aetiology Modified KDOQI staging

(section 2.5)

Risk of progression

(section 3)

Evidence of progression Complications

Blood pressureAnaemiaBone diseaseAcidosis

D

Figure 1: Example algorithm for screening, assessment and diagnosis of patients with

chronic kidney disease

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3 4

This section examines the evidence for the effectiveness of interventions in slowing the rate of

progression of CKD or reducing cardiovascular risk Some interventions have additive effects

blood pressure will affect proteinuria and a reduction in both is often achieved by agents

that may have an independent effect on GFR Much of the evidence for the assessment of the

effects of blood pressure or proteinuria reduction are sub-analyses of studies designed to assess

the effect of a specific drug intervention and it is important to determine that the effect seen

is drug-independent Similarly, studies suggesting a specific drug effect on CKD progression

must account for changes in blood pressure and proteinuria achieved in the treatment group

compared to the control group

People with chronic kidney disease are at significantly increased risk of cardiovascular events

In a pooled analysis of four large community based, longitudinal studies, CKD (GFR between

15-60 ml/min/1.73 m2) was associated with a 20% increased risk of cardiovascular events and

death Cardiovascular risk was particularly high in black individuals (75% increase), compared with

whites (13%).100 Patients with ESRD have a very high prevalence of cardiovascular disease

Outwith the context of CKD, the benefits of lipid lowering therapy, antihypertensive and

antiplatelet therapy in terms of cardiovascular disease risk reduction have been demonstrated

consistently in large randomised controlled trials.19

Patients with CKD are often prescribed medications for comorbid conditions, such as diabetes

All drug dosages should be adjusted for kidney function, where appropriate Drugs with

potentially adverse effects on kidney function or complications of decreased kidney function

should be discontinued if possible.101 Information on drug dosage alteration is available in The

Renal Drug Handbook, 2nd Edition.124 Information on whether drugs are contraindicated in

CKD is available in the current british National Formulary (bNF)122 and summary of product

characteristics (SPC).123

3.1 loWering BlooD Pressure

High blood pressure is very common in CKD and represents a major target for intervention to

prevent progression.125 There is a strong epidemiological relationship between blood pressure

and cardiovascular disease and meta-analyses of randomised controlled trials (RCTs) in the

general population have demonstrated that the benefits of antihypertensive therapy are primarily

a consequence of the level of blood pressure control attained rather than the specific agents

used.132 Multiple antihypertensive agents are routinely required in the management of blood

pressure in patients with CKD

3.1.1 REDUCING THE PROGRESSION OF CHRONIC KIDNEY DISEASE

Analysis of blood pressure (bP) effects on renal outcomes in trials of antihypertensive therapy

underlines the importance of blood pressure reduction in delaying the progression of CKD.133-138

In a meta-analysis of 20 RCTs including over 50,000 patients with CKD the risk of ESRD reduced

with each tertile of bP control, independent of the agent used The group with the highest tertile

of bP reduction (-6.9 mmHg (-9.1 to -4.8) had a relative risk of ESRD of 0.74 (0.59 to 0.92).138

A systolic bP of >130 mmHg is significantly associated with CKD progression in non-diabetic

patients with proteinuria of >1 g/day This meta-analysis identified the optimal systolic bP as

110-129 mmHg.136 This study suggested that for patients with proteinuria, systolic bPs of <110

mmHg may be associated with a more rapid decline in GFR

A meta-analysis of 55 RCTs in CKD patients (n=5,714) demonstrates a clear association between

reduction in bP and reduction in albuminuria.138 The effect of blood pressure on proteinuria is

greater in patients with higher baseline levels of urinary protein excretion.133

a Blood pressure should be controlled to slow the deterioration of glomerular filtration rate and reduce proteinuria Patients with ≥1 g/day of proteinuria (approximately

equivalent to a protein/creatinine ratio of 100 mg/mmol) should have a target maximum systolic blood pressure of 130 mmhg

3.2 reDucing Proteinuria

3.2.1 REDUCING THE PROGRESSION OF CHRONIC KIDNEY DISEASE

Proteinuria is associated with progression of CKD and has been linked to cardiovascular risk.139

It can be modified by blood pressure reduction Some antihypertensive drugs may have an antiproteinuric effect in addition to their antihypertensive effects

One meta-analysis and five post hoc analyses of RCTs assessed the relationship between proteinuria and the progression of CKD, measured by change in GFR, doubling of serum creatinine or progression to ESRD The analyses include patients with diabetic and non-diabetic renal disease, all with proteinuria A higher baseline proteinuria was shown to be predictive of CKD progression and a reduction in proteinuria reduced the relative risk of CKD progression.133,137,140-143

For example, a baseline urinary protein excretion (UPE) of <1.1 g/day confers a 7.7% risk of ESRD at three years For baseline UPE of 2 to 4 g/day; this risk rises to 22.9% and at >8 g/day, the risk of ESRD is 64.9%.137

In a meta-analysis of 11 RCTs in patients with non-diabetic CKD (1,860 patients), a 1 g/day reduction in UPE was associated with an 80% reduction in the risk of CKD progression/ESRD (RR 0.20; 95% CI 0.13 to 0.32).133 In patients with type 2 diabetes, for each halving of the degree of proteinuria in the first year of follow up, the risk of ESRD at three years was reduced

by 56% (hazard ratio HR = 0.44; 95% CI 0.40 to 0.49).137

Any reduction in proteinuria in patients with CKD will lower the relative risk of disease progression, although patients with higher degrees of proteinuria will benefit more There should be no lower target as the greater the reduction from baseline urinary protein excretion, the greater the effect on slowing the rate of loss of GFR.133,137,143

a Patients with chronic kidney disease and proteinuria should be treated to reduce proteinuria.

3.3 angiotensin converting enZyme inhiBitors anD angiotensin

recePtor Blockers

Angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin II receptor blockers (ARbs) confer both cardioprotective and renoprotective effects ACE inhibitors and ARbs preferentially dilate the efferent renal arteriole reducing intraglomerular hypertension and reducing proteinuria independent of systemic blood pressure effects

3.3.1 REDUCING THE PROGRESSION OF CHRONIC KIDNEY DISEASE

Twelve meta-analyses have examined the effects of ACE inhibitors and ARbs in diabetic and diabetic patients with CKD on urinary protein excretion and CKD progression.134-136,138,144-151

non-microalbuminuria in diabetes mellitus

Twenty five to forty per cent of patients with diabetes develop diabetic nephropathy.152,153

Microalbuminuria identifies the population at risk of progressive diabetic nephropathy Having two out of three urine samples positive for microalbuminuria (30-300 mg /day albumin) is viewed as incipient diabetic nephropathy.16

Prevention or regression of albuminuria is a key target in the treatment of early diabetic kidney disease

1 ++

1 ++

1 ++

1 ++

ACE inhibitors can prevent the development of diabetic nephropathy (microalbuminuria)149 and are

able to regress microalbuminuria to no albuminuria.134,144 ACE inhibitors can also reduce the rate

of progression of microalbuminuria to macroalbuminuria134,144,145 and reduce albuminuria.138,146

ARbs can reduce the rate of progression of microalbuminuria to macroalbuminuria and regress

microalbuminuria to no albuminuria144 and can reduce albuminuria.138

In three meta-analyses, the beneficial effects of ACE inhibitors on albuminuria could not be fully

explained by reduction of blood pressure.134,138,149 In the other meta-analyses, the independence

of effect of ACE inhibitors on AER from effect on bP could not be established either because

of lack of data or the analyses not achieving statistical significance.144-146

Prevention of microalbuminuria

One meta-analysis of 16 trials (7,603 patients) demonstrated that ACE inhibitors prevent

the development of diabetic kidney disease in patients with no microalbuminuria (albumin

excretion <30 mg/day) at baseline.149 This effect appears to be present in patients with or

without hypertension, patients with type 1 or type 2 diabetes, and patients with or without

normal GFR

regression of microalbuminuria to no albuminuria in diabetes mellitus

ACE inhibitors and ARbs can cause microalbuminuria to regress to no albuminuria in diabetes

mellitus.134,144 A meta-analysis of 36 RCTs (1,888 patients) demonstrated that ACE inhibitors

increased the likelihood of regression from microalbuminuria to no albuminuria (RR 3.42;

95% CI 1.95 to 5.99) in patients with type 1 or 2 diabetes, both normotensive and with

pre-existing hypertension In patients with type 2 diabetes with hypertension, ARbs also increased

the likelihood of regression from microalbuminuria to no albuminuria (RR 1.42; 95% CI 1.05

to 1.93), although this analysis did not correct for the bP lowering effects of these drugs.144 A

smaller meta-analysis of 12 RCTs (689 patients) demonstrated an odds ratio for regression to

no albuminuria of 3.07 (95% CI 2.15 to 4.44) for patients treated with ACE inhibitors; an effect

attenuated but not abolished by adjusting for blood pressure, suggesting a specific antiproteinuric

effect of these drugs.134

Progression of microalbuminuria to macroalbuminuria in diabetes mellitus

There is a reduction in the rate of progression of microalbuminuria to macroalbuminuria in

patients with diabetes treated with ACE inhibitors or ARbs.134,144,145 A meta-analysis in patients

with type 1 or type 2 diabetes in primary care demonstrated that ACE inhibitors (36 RCTs, 2,010

patients) reduced the rate of progression of micro to macroalbuminuria by 45%, and ARbs

(four RCTs, 761 patients, type 2 diabetes only) by 51% regardless of the presence or absence

of baseline hypertension, diabetes type, or duration of treatment (ACE inhibitors: RR 0.55;

95% CI 0.28 to 0.71, ARbs: RR 0.49; 95% CI 0.32 to 1.05) ACE inhibitors and ARbs were not

significantly different in their effects on progression of microalbuminuria The analysis did not

correct for bP effects of these drugs.144

A meta-analysis of 12 RCTs in normotensive patients with type 1 diabetes (689 patients)

demonstrated that the reduction in progression of micro to macroalbuminuria (OR for progression

0.38; 95% CI 0.25 to 0.57) with ACE inhibitors was attenuated when blood pressure effects

were adjusted for but not abolished suggesting a bP independent effect of ACE inhibitors on

microalbuminuria.134

ACE inhibitors and ARbs reduce albuminuria in patients with diabetes146 and reduce proteinuria

ranging from microalbuminuria to overt proteinuria (7.2 to 3,000 g/day albuminuria) All the

RCTs included had an active control arm in respect of bP No difference in blood pressure was

noted between the treatment groups to explain the reduction in albumin excretion rate.138

a Patients with chronic kidney disease and type 1 diabetes with microalbuminuria should

be treated with an angiotensin converting enzyme inhibitor irrespective of blood

pressure.

a Patients with chronic kidney disease and type 2 diabetes with microalbuminuria should

be treated with an angiotensin converting enzyme inhibitor or an angiotensin receptor

blocker irrespective of blood pressure.

Proteinuria reduction in non-diabetic patients with ckD

Three meta-analyses in non-diabetic patients with CKD show a reduction in overt proteinuria with ACE inhibitors or ARbs.135,138,147 In a meta-analysis of eight RCTs (142 patients) in patients with polycystic kidney disease and proteinuria, ACE inhibitors reduced proteinuria significantly after correction for baseline and subsequent changes in bP The reduction was greater at higher baseline proteinuria levels.147

a angiotensin converting enzyme inhibitors and angiotensin receptor blockers are the agents of choice to reduce proteinuria in patients without diabetes but who have chronic kidney disease and proteinuria.

rate of progression of ckD in patients with and without diabetes

There is conflicting evidence regarding the role of ACE inhibitors and ARbs in reducing the rate of progression of CKD.135,136,145,148

In a meta-analysis of 7 RCTs including 1,389 patients with established proteinuria, ACE inhibitors reduced the risk of CKD progression or the numbers reaching ESRD by 40% (RR 0.60; 95% CI 0.49 to 0.73)145 In a meta-analysis of 10 RCTs in 1,594 patients without diabetes, ACE inhibitors reduced the risk of ESRD by 30% (RR 0.70; 95% CI 0.51 to 0.97).148 Neither of these analyses could separate the effect of ACE inhibitors on CKD progression from their effect on bP In a meta-analysis of 11 RCTs in 1,860 patients with non-diabetic kidney disease, ACE inhibitors reduced the risk of ESRD or doubling of serum creatinine after adjusting for baseline and follow

up bP and proteinuria (RR of ESRD in ACE inhibitor group 0.69; 95% CI 0.51 to 0.94, doubling

of serum creatinine /ESRD combined 0.70; 95% CI 0.55 to 0.88)

Further analysis of this cohort of patients has demonstrated that there was no additional benefit

of ACE inhibitors over other blood pressure treatments for patients with a baseline urinary protein excretion of<0.5 g/day.154

Conflicting results were reported in three meta-analyses.138,144,147

In one meta-analysis (142 patients) whilst a significant reduction in proteinuria was demonstrated

in patients with autosomal dominant polycystic kidney disease (ADPKD) treated with ACE inhibitors, only a trend to slowing CKD progression was seen, which was greater in patients with higher baseline proteinuria levels.147 The mechanism underlying cyst formation is not affected by blood pressure

In a meta-analysis of 36 RCTs in patients with type 1 or 2 diabetic nephropathy in primary care, the point estimate for developing ESRD or the doubling of serum creatinine was less in patients who were prescribed ACE inhibitors but not statistically significant (all cause mortality RR 0.64; 95% CI 0.40 to 1.03: doubling of serum creatinine RR 0.60; 0.35 to 1.05) This included the micro-HOPE study accounting for over half the patients in the analysis and which recruited patients with a high cardiovascular risk and mortality but relatively low renal risk This study alone produced opposite findings to the others in the meta-analysis (ie favoured placebo/no treatment), but, because of its size, accounted for 29% of the weighting of the overall result Angiotensin receptor blockers did significantly reduce the risk of an adverse renal outcome in patients with type 2 diabetes (ESRD: RR 0.78; 95% CI 0.67 to 0.91: doubling of serum creatinine:

RR 0.79; 95% CI 0.67 to 0.93).144

A meta-analysis of 13 RCTs in 37,089 patients did demonstrate a reduction in the risk of ESRD

in patients on ACE inhibitors or ARbs (RR 0.87) although no benefit was demonstrated in the diabetic sub-population blood pressure was not different between the ACE inhibitor/ARb and comparison group The analysis included 33,357 patients in the ALLHAT trial, where the 24,303 patients in the control group assigned thiazides had an approximately 2 mmHg lower systolic

bP at the end of the study, which could have attenuated any benefits of ACE inhibitors This individual study heavily weighted the overall outcome of the analysis in a direction contrary to the other RCTs analysed In the 11 RCTs (3,376 patients) with doubling of serum creatinine as

a renal outcome, a non-significant reduction in risk was observed in patients on ACE inhibitors/ARbs (RR 0.71; 95% CI 0.49 to 1.04) with no benefit in the diabetic sub-population The meta-analysis did not assess the effects of ACE inhibitors or ARbs individually.138

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combination treatment with ace inhibitors and arBs

Two meta-analyses have looked at the effect of adding ARb treatment to ACE inhibitors in

patients with CKD.150,151 These show that combination treatment reduces proteinuria more than

ACE inhibitors alone in both patients with diabetic and non-diabetic kidney disease The role

of blood pressure reduction in this effect is not clear.151 The use of sub-maximal doses of the

drugs limited the validity of conclusions.150 Only one study in these meta-analyses studied the

ability of the combination to slow CKD progression and suggested that the combination was

better.150 In one meta-analysis hyperkalaemia was increased overall by a small but significant

amount (0.11 mmol/l, 95% CI 0.05 to 0.17 mmol/l).151 In the other meta-analysis, clinically

significant hyperkalaemia occurred in only 19 out of 434 patients, suggesting this is a safe

combination, if monitored.150

More data are required to determine the effect of combination therapy on disease progression

before it will be possible to make a recommendation on this treatment

a angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers should

be used as agents of choice in patients (with or without diabetes) with chronic kidney

disease and proteinuria (≥0.5 g/day, approximately equivalent to a protein/creatinine

ratio of 50 mg/mmol) in order to reduce the rate of progression of chronic kidney

disease.

3.3.2 REDUCING THE RISK OF CARDIOvASCULAR DISEASE

There are limited data on the specific impact of antihypertensive therapy on cardiovascular

outcomes in people with CKD In a systematic review of 50 randomised trials of ACE inhibitor

and/or ARb therapy in people with diabetic nephropathy, neither agent was associated with

a significant overall reduction in mortality A subgroup analysis of studies using full-dose ACE

inhibitor therapy compared with studies using half or less than half of the maximum dose

showed that full dose therapy was associated with a 22% reduction in all-cause mortality.155 This

finding was confirmed by another RCT which showed that an ACE inhibitor reduced all-cause

mortality by 21% in people with diabetic nephropathy, independently of the modest effect on

blood pressure reduction while ARbs had no effect on mortality.156

In the Anglo Scandinavian Cardiac Outcomes Trial (ASCOT), a blood pressure regimen

incorporating amlodipine and perindopril was associated with fewer cardiovascular events in

patients with CKD, than a regimen incorporating atenolol and bendroflumethiazide.157

In the Survival and ventricular Enlargement trial (SAvE), CKD was associated with an

increased risk of cardiovascular events after myocardial infarction, particularly when GFR was

<45 ml/min/1.73 m2 Subjects randomised to captopril post-myocardial infarction had a reduced

risk of cardiovascular events, compared with placebo, irrespective of baseline renal function

Patients with CKD accrued greater absolute benefit with 12.4 cardiovascular events prevented

per 100 subjects with CKD, compared with 5.5 events per 100 subjects without CKD.158

3.3.3 ADvERSE EFFECTS OF RENIN ANGIOTENSIN SYSTEM bLOCKADE

Hyperkalaemia (>5.5 mmol/l) is a recognised consequence of ACE inhibitor and ARb therapy

and can occur independently at various stages of CKD

Renin angiotensin system blockade can cause a decline in GFR in the context of low renal

perfusion Low renal perfusion can occur acutely, eg volume depletion, or chronically,

eg renovascular disease or low cardiac output states (severe heart failure or outflow tract

obstruction)

It is not always necessary to discontinue ACE inhibitor/ARb therapy if GFR declines following

initiation or dose increase, providing the fall in GFR is less than 20% and renal function

stabilises Similarly, modest, stable hyperkalaemia may be preferable to discontinuing a useful

3.4 non-DihyDroPyriDine calcium channel Blockers

3.4.1 REDUCING THE PROGRESSION OF CHRONIC KIDNEY DISEASE

One meta-analysis in patients with hypertension and proteinuria concluded that dihydropyridine calcium channel blockers (CCbs), but not other CCbs, reduce proteinuria.159 Although bP changes were the same, the independence of effect on proteinuria from that of

non-bP reduction was not statistically significant An effect on disease progression could not be assessed

a non-dihydropyridine calcium channel blockers should be considered in patients with chronic kidney disease and proteinuria who are intolerant of angiotensin converting enzyme inhibitors or angiotensin receptor blockers.

3.5 liPiD loWering

There are no published large scale RCTs of the effect of lipid-lowering therapy on cardiovascular disease or renal outcomes, specifically in people with stage 1-3 CKD Data are available from subgroup analyses of the major statin trials and one RCT of fibrate therapy The Study of Heart and Renal Protection (SHARP) is currently recruiting 9,000 patients with CKD (6,000 pre-dialysis patients and 3,000 undergoing dialysis) and will examine the effects of therapy with simvastatin and ezetimibe (a cholesterol absorption inhibitor) on cardiovascular and renal outcomes.160

3.5.1 REDUCING THE PROGRESSION OF CHRONIC KIDNEY DISEASE

Dyslipidaemia may contribute to progression of renal disease by intrarenal atherosclerosis or direct toxicity to renal cells.161,162 The use of statins (HMG-CoA reductase inhibitors) to reduce serum cholesterol may slow the progression of CKD Statins may have a renoprotective effect that is not dependent on lipid lowering,163 and appear to have an additional anti-inflammatory effect.164

Four systematic reviews of the use of statins in slowing the progression of CKD were found Two were of low methodological quality.165,166

In a study investigating the rate of kidney function loss in patients with stages 1-3 CKD, pravastatin reduced the rate of decline in renal function by 34% in patients with stage 3 CKD (0.22 ml/min per 1.73 m2/year, p=0.002).167

In a meta-analysis including 39,704 patients from 27 studies,168 statins reduced the rate of decline of GFR by 1.22 ml/min/yr (95% CI 0.44 to 2.00 ml/min/yr) This benefit was only 0.22 ml/min/yr when the analysis was restricted to well performed trials, and the only subgroup

in which the effect of statins on GFR proved to be significant was patients with cardiovascular disease

Two meta-analyses examined reduction in proteinuria with statin treatment One demonstrated

a non-significant favourable change168 while the second demonstrated a significant reduction

in microalbuminuria of 48% (95% CI 71% to 25%) and proteinuria of 47% (95% CI 67% to 26%) The effect was greatest with higher degrees of proteinuria.169

3.5.2 REDUCING THE RISK OF CARDIOvASCULAR DISEASE

In the population without CKD, therapy with statins reduces the five year incidence of major coronary events, coronary revascularisation and stroke by about 20% for every mmol/l reduction

in low density lipoprotein (LDL) cholesterol This is largely irrespective of initial lipid profile, but absolute risk reduction relates to baseline absolute risk and the reduction in LDL cholesterol achieved.170,171

Consideration for statin therapy is also indicated for individuals aged over 40 years whose 10-year

cardiovascular risk is calculated to be ≥20%.19 Current cardiovascular risk assessment tools,

such as the joint british Societies CvD risk prediction chart72 do not include CKD in their risk

prediction algorithm and so underestimate cardiovascular risk in people with CKD (see SIGN

guideline 97 on risk estimation and the prevention of cardiovascular disease).19 The majority

of older adults with stage 3 CKD should be considered as having a 10-year cardiovascular risk

in excess of 20%.19 Individuals with stage 1 and 2 CKD may cross this threshold if they have

other risk factors for cardiovascular disease

Patients with mild to moderate CKD should, in theory, accrue greater absolute benefit from statin

therapy, because of their higher absolute risk In contrast, observational studies among dialysis

patients have reported a negative association between total cholesterol and mortality.173 RCTs

of statin therapy in patients with advanced CKD (ie haemodialysis or post-transplant patients)

showed no overall benefit on cardiovascular outcomes.174,175 There are also concerns about the

potential toxicity of long term statin therapy in people with CKD

Pravastatin (40 mg daily) reduced cardiovascular outcomes by 23% in a meta-analysis of three

RCTs including 4,491 patients with moderate CKD (mean GFR 55 ± 8 ml/min).167 Over 70%

had coronary heart disease at baseline, but the relative risk reduction was the same in people

with or without coronary disease The overall risk reduction was comparable with patients who

had normal kidney function, but the absolute benefit accrued by the CKD patients was greater

because of their higher baseline risk

In another study, atorvastatin (10 mg daily) reduced cardiovascular events by 40% in patients

with CKD (serum creatinine up to 200 micromol/l) over five years.176 All patients in the primary

study had hypertension, at least three other cardiovascular risk factors and a total cholesterol

<6.5 mmol/l Gemfibrozil (1,200 mg daily) reduced cardiovascular events by 27% in patients

with mild to moderate CKD (GFR 30-75 ml/min/1.73 m2), low high density lipoprotein (HDL)

cholesterol concentrations and a prior history of cardiovascular disease.177 There was no overall

difference in adverse events between the gemfibrozil and placebo arms, but gemfibrozil was

associated with an increased risk of sustained increase in serum creatinine compared with

placebo (5.9% vs 2.8%)

B statin therapy should be considered in all patients with stage 1-3 chronic kidney disease,

with a predicted 10-year cardiovascular risk ≥20%.

3.6 antiPlatelet theraPy

3.6.1 REDUCING THE RISK OF CARDIOvASCULAR DISEASE

Aspirin (or other antiplatelet therapy) reduces cardiovascular events by 25% in patients at

increased cardiovascular risk in the general population.178 Aspirin is indicated both for patients

with established cardiovascular disease and, as primary prevention, in individuals at high

estimated risk of cardiovascular disease.172 There are no data from large scale RCTs specifically

in patients with stage 1-3 CKD In the UK-HARP-1 study, aspirin therapy was associated with

a threefold increased risk of minor, although not major bleeding in a heterogeneous group of

patients with advanced CKD (242 pre-dialysis patients with serum creatinine ≥150 micromol/l;

73 patients on dialysis and 133 post-transplant patients).179 The substantial benefit of aspirin

therapy in terms of cardiovascular disease risk reduction must be weighed against the risk of

potential adverse effects

B low-dose antiplatelet therapy should be considered in all patients with stage 1-3 chronic

kidney disease, whose estimated 10-year cardiovascular risk is ≥20%.

Stages 1-3 chronic kidney disease

Four small RCTs (n=69-131) conducted in patients with stages 2-3 CKD and diabetes (type 1 and type 2) did not demonstrate a beneficial effect of protein restriction (0.6-0.8 g/kg) on delaying disease progression.180-183 These studies followed up patients for one to four years

One small RCT (n=89) in non-diabetic patients with stage 3 CKD conducted over 12 months demonstrated a positive effect of protein restriction (0.6 g/kg/day) on progression (p<0.01) Compliance in the restricted group was suboptimal, the protein intake in the control group was 2.3 times higher than in the restricted group (0.67 g vs 1.54 g) and a significant decline

in energy intake coupled with a deterioration (body weight and bMI) were seen in the protein restricted group (p<0.05).183

Stage 4 chronic kidney disease

For non-diabetic and diabetic patients with stage 4 CKD two systematic reviews and one analysis suggest that, in comparison to other treatments, there is, at most, a modest benefit associated with restricting protein leading to a delay in CKD progression (0.53 ml/min/year; 95% CI 0.08 to 0.98 ml/min/year).184-186

meta-There are many limitations to these studies; they include stage 5 CKD patients; the original studies are heterogeneous in nature (CKD diagnosis, duration of intervention, varying levels of protein restrictions), few studies used GFR as an outcome; several studies specifically excluded patients receiving ACE inhibitors; compliance with protein restriction was suboptimal; the effect

of restriction on nutritional status was largely ignored, smaller studies reported greater effects and funnel plots indicate a publication bias in favour of protein restricted diets

In clinical practice any benefits of protein restriction have to be offset against the potential detrimental effects on nutritional status; the difficulties of patient compliance, potential effects

on quality of life and the costs associated with implementation and monitoring

It is not possible to deduce an optimal protein level from the available evidence High protein intakes are associated with high phosphate intakes as foods that contain protein also tend to contain phosphate.183 It would appear prudent to avoid high protein intakes in stage 4 CKD patients when hyperphosphatemia is prevalent162 and this should be done under the guidance

of an appropriately qualified dietitian

a Dietary protein restrictions (<0.8 g/kg/day) are not recommended in patients with

early stages of chronic kidney disease (stages 1-3).

; In stage 4 chronic kidney disease patients high protein intake (>1.0 g/kg) is not

One systematic review looked for the evidence linking dietary salt intake and progression

of chronic kidney disease.188 The available evidence consists of small scale studies of short duration and poor quality There is a suggestion that dietary salt consumption directly links

to albuminuria but no consistent evidence regarding the effect of dietary sodium intake on progression of kidney disease